Mitochondrial DNA (mtDNA) haplogroups can affect mitochondrial function, and have been associated with diabetes in the general population. IR and DM occur more frequently in persons with HIV infection, and are important causes of morbidity and mortality despite effective antiretroviral therapy (ART). In analyses of the Multicenter AIDS Cohort Study (MACS), HIV-infected men had a significantly greater risk of IR and DM than HIV-seronegative men. The pathophysiology of these complications is not well established. Adiponectin is an adipocyte-derived hormone with diverse beneficial properties, and is related to mitochondrial function. Low adiponectin is associated with IR and DM in the general population, and is common in HIV-infected persons. We believe HIV-infection and ART create a milieu of mitochondrial damage and abnormal glucose metabolism, thus establishing a population enriched with diabetes-related phenotypes, including hypoadiponectinemia and IR. Mitochondrial DNA haplogroups have been associated with HIV- and ART-related adverse outcomes. Although no studies have assessed relationships between mtDNA variation and DM in HIV-infected persons, recent studies found associations between mtDNA variants, IR and adiponectin, suggesting that adiponectin dysregulation may be a novel mechanism by which mtDNA variation influences IR and DM. A co-investigator on this proposal has developed algorithms to derive haplogroups using genome-wide association study (GWAS) data from common platforms, enabling us to utilize available genome-wide genotype data in addition to existing mtDNA haplogroup data to perform secondary analyses of associations between haplogroups and diabetes-related phenotypes in MACS. We will also generate new mtDNA haplogroup data for the majority of MACS participants, increasing our analysis sample sizes. Our hypotheses are that the risk of IR and DM is: (a) associated with mtDNA haplogroups; (b) accentuated by additional mitochondrial stressors of chronic HIV infection and ART; and (c) mediated by adiponectin and adipocyte mitochondrial function. We will test these hypotheses in the following aims: 1) Determine associations between mtDNA haplogroups and prevalent and incident DM among MACS participants; 2) Determine associations between mtDNA haplogroups and IR among MACS participants of European ancestry; 3) Explore associations between mtDNA haplogroups and circulating adiponectin levels in HIV-infected and uninfected MACS participants; and 4) Explore associations between mtDNA haplogroups and adipose mitochondrial function, adiponectin levels, and IR in HIV seropositive clinical trial participants before and during ART. The proposed secondary analyses in this project will use innovative methods to obtain mtDNA haplogroups from existing genome-wide genotype data, will include novel analyses of serum adiponectin and adipose mitochondrial function, and will directly inform future studies of interventions to prevent and/or treat IR and DM in HIV-infected and uninfected populations.